This project is focused on the clinical study of patients with AIDS-related malignancies and related diseases. Much of the work is focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). These tumors almost exclusively developin HIV-infected patients, and the vast majority of our patients have HIV infection. This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans disease (MCD). We are conducting a trial of pomalidomide in KS, and preliminary results indicate that it has substantial activity. We have also initiated a follow-up trial to study the combination of pomalidomide and liposomal doxorubicin in patients with more severe KS. We have initiated a clinical trial to study the natural history of KSHV-associated multicentric Castleman's disease (KSHV-MCD) and to explore various treatments. Some of the treatments include the combination of AZT and valganciclovir, a pro-drug of ganciclovir; liposomal doxorubicin and rituximab; and tocilizumab, a monoclonal antibody against the intrleukin-6 receptor. Results show that AZT plus valganciclovir has substantial activity, although relapses are common when used alone. In addition, we are studying other patients with KSHV infection to assess factors that may be linked to malignancy. We are exploring methotrexate-based therapy for primary central nervous system lymphoma (PCNSL). We have identified a group of patients with a new KSHV-related syndrome, called KSHV inflammatory cytokine syndrome (KICS), and opened a protocol to study this new disease. As part of this study, we are testing several possible therapies. We are collaborating with a number of other investigators to conduct translational studies related to HIV, AIDS-malignancies. In collaboration with the Cancer Immunotherapy Trials Network, we have initiated a phase I and feasibility trial of the anti-PD-1 inhibitor pembrolizumab in HIV-infected patients with a wide range of malignancies. Finally, based in part on our in vitro data showing that pomalidomide prevents KSHV-induced downregulation of MHC-1 and other immunologic surface markers, we have initiated a trial of lenalidomide, rituximab, and infusional chemotherapy for patients with primary effusion lymphoma. We are planning several other pathogenesis-bases trials of HIV-associated malignancies.